Solid state forms of ixazomib citrate

Abstract

The present disclosure encompasses solid state forms of Ixazomib Citrate and pharmaceutical compositions thereof. Also disclosed are processes for preparation of Ixazomib Citrate.

The invention claimed is: 
     
       1. A process for preparation of Ixazomib Citrate having low levels of residual solvents comprising A) providing crystalline form F of Ixazomib Citrate and B) converting crystalline form F of Ixazomib Citrate to Ixazomib Citrate having low levels of residual solvents. 
     
     
       2. The process according to  claim 1 , wherein form F, is obtained by a process comprising:
 i) providing 2,5-Dichloro-N-[2-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl] amino]-2-oxoethyl] benzamide, citric acid, acetone and HCl; 
 ii) optionally concentrating the reaction mixture; 
 iii) optionally seeding with Ixazomib Citrate form 2; 
 iv) optionally diluting and/or optionally stirring; and 
 v) optionally cooling and keeping at low temperature until crystallization is complete. 
 
     
     
       3. The process according to  claim 2 , wherein in step i) the amount of HCl may be less than equimolar amount, less than about 50 mol %, less than about 30 mol %, less than about 20 mol %, less than about 10 mol %, or less than about 5 mol % with respect to the starting material, 2,5-Dichloro-N-[2-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutyl] amino]-2-oxoethyl] benzamide. 
     
     
       4. The process according to  claim 1 , wherein form F, is obtained by a process comprising:
 a) providing Ixazomib Citrate in THF; 
 b) warming the mixture to a temperature of about 40 to about 60° C. and stirring until dissolution; 
 c) concentrating the mixture under vacuum to minimal volume; 
 d) dissolving the residue in acetone; and 
 e) optionally seeding with crystalline Ixazomib Citrate or stirring until spontaneous crystallization occurs. 
 
     
     
       5. The process according to  claim 1 , wherein step B) comprises a step of filtering the reaction mixture and drying to afford Ixazomib Citrate. 
     
     
       6. The process according to  claim 1 , wherein form F is substantially free of any other form of Ixazomib Citrate. 
     
     
       7. The process according to  claim 1 , wherein the obtained Ixazomib citrate is form 2 of Ixazomib Citrate. 
     
     
       8. The process according to  claim 2 , wherein the obtained Ixazomib citrate is form 2 of Ixazomib Citrate. 
     
     
       9. The process according to  claim 3 , wherein the obtained Ixazomib citrate is form 2 of Ixazomib Citrate. 
     
     
       10. The process according to  claim 4 , wherein the obtained Ixazomib citrate is form 2 of Ixazomib Citrate. 
     
     
       11. The process according to  claim 5 , wherein the obtained Ixazomib citrate is form 2 of Ixazomib Citrate. 
     
     
       12. The process according to  claim 6 , wherein the obtained Ixazomib citrate is form 2 of Ixazomib Citrate.